The role of DNA demethylase TET in Treg/Th17 differentiation.
| Project/Area Number |
20K07541
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 49070:Immunology-related
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| Research Institution | Chiba University (2022)
Keio University (2020-2021) |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | DNAメチル化 / Th17細胞 / 制御性T細胞 / エピジェネティクス / TET / 腸内細菌 / AhR / Treg / Tfh細胞 / T細胞分化 / 自己免疫疾患 |
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| Outline of Research at the Start |
DNAメチル化を含む染色体のエピジェネティック修飾は細胞の分化やがん化に密接に関与するが、免疫応答におけるDNAメチル化／脱メチル化の制御機構とその意義は明らかではない。これまでにDNA脱メチル化酵素であるTET (Ten-eleven translocation)をT細胞特異的に欠損するマウスを用い、Tetが制御性T細胞（Treg）のFoxp3安定化と末梢でのTreg/Th17分化に重要な役割を果たすことを見出した。本研究ではTETが制御するヘルパーT細胞分化に関与する遺伝子を明らかにし、DNA脱メチル化のT細胞分化の安定性と可塑性における意義を解明することを目指す。
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| Outline of Final Research Achievements |
Ten-eleven translocation (TET) proteins regulate DNA methylation and gene expression. Previously we found that T cell-specific Tet2 and Tet3 double-knockout (Tet2f/fTet3f/fCd4-Cre; DKO) mice displayed splenomegaly and lymph adenopathy accompanied by uncontrolled activation of T cells which exhibited Th17- and/or follicular helper T (Tfh)-like phenotypes. In this study, we revealed that Tet2 and Tet3 regulate Treg/Th17 differentiation in the periphery. We found that Tet regulates Treg/Th17 differentiation via AhR signaling by gut microbiota-dependent tryptophan metabolites. Furthermore, gene expression and methylation analysis revealed that Tet regulates Th17 differentiation through DNA methylation of the Rara and Bach2 genes.
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| Academic Significance and Societal Importance of the Research Achievements |
これまでヘルパーT細胞の分化機構に関しては転写ネットワークによる制御機構に関する報告が多くなされてきたが、エピジェネティック制御による調節機構についての研究は端緒についたばかりである。本研究では、Tetによる末梢でのTreg/Th17分化制御機構について明らかとし、本研究がさらに発展すれば、免疫疾患、炎症性疾患やがんの新規治療法確立への応用が期待される。
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Report
(4 results)
Research Products
(12 results)
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[Journal Article] Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation.2022
Author(s)
Park SA, Lim YJ, Ku WL, Zhang D, Cui K, Tang LY, Chia C, Zanvit P, Chen Z, Jin W, Wang D, Xu J, Liu O, Wang F, Cain A, Guo N, Nakatsukasa H, Wu C, Zhang YE, Zhao K, Chen W.
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Journal Title
Nat Commun.
Volume: 13(1)
Issue: 1
Pages: 6069-6069
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] The Curcumin Analog GO-Y030 Controls the Generation and Stability of Regulatory T Cells2021
Author(s)
Takashi MaruYama, Shuhei Kobayashi, Hiroko Nakatsukasa, Yuki Moritoki, Daiki Taguchi, Yoichi Sunagawa, Tatsuya Morimoto, Atsuko Asao, Wenwen Jin, Yuji Owada, Naoto Ishii, Yoshiharu Iwabuchi, Akihiko Yoshimura, WanJun Chen, Hiroyuki Shibata
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Journal Title
Frontiers in immunology
Volume: 12
Pages: 687669-687669
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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